MINIMAL FOLIATIONS FOR THE HIGH-DIMENSIONAL FRENKEL-KONTOROVA MODEL

For the high-dimensional Frenkel-Kontorova(FK)model on lattices,we study the existence of minimal foliations by depinning force.We introduce the tilted gradient flow and define the depinning force as the critical value of the external force under which the average velocity of the system is zero.Then,the depinning force can be used as the criterion for the existence of minimal foliations for the FK model on a Z^(d)lattice for d>1.

A CRISPR-Cas9 screen shows the combination efficacy of lenvatinib plus epidermal growth factor receptor inhibitors for treatment of liver cancer

Recently,in cooperation with the Netherlands Cancer Institute,we demonstrated that epidermal growth factor receptor(EGFR)activation limited the response of liver cancer to lenvatinib.The original article was published in Nature as a cover story,which resulted in considerable attention from major scientific journals.Here,we were invited by Cancer Biology&Medicine to provide comments on preclinical and clinical findings about the combination of lenvatinib plus EGFR inhibitors as a promising strategy for hepatocellular carcinoma(HCC)treatment.Primary liver cancer represents the sixth most common malignancy and the third leading cause of cancer-related mortality worldwide,with an estimated 906,000 new cases and 830,000 deaths in 20201.

Combating inconsistent evaluation of intra-tumor immune status by a novel transcriptomic signature in hepatocellular carcinoma

Dear Editor,Harnessing the power of the immune system via immune checkpoint inhibition has revolutionized the treatment paradigm of many malignancies,including hepatocellular carcinoma(HCC).1 Despite encouraging efficacy seen with the immune checkpoint blockade(ICB)agents in a subset of patients with HCC,however,there remain a large number of HCC patients experience ICB resistance and failed to derive durable benefit from these agents.

MicroRNAs in hypoxia and acidic tumor microenvironment

MicroRNAs(miRNAs)are short non-coding RNAs of*22 nucleotides that play important roles in diverse biological functions including tumor adaption,survival,and metabolism homeostasis in specific tumor microenvironment,such as hypoxia and low pH.Hypoxia is a unique physiological condition during tumor development and progression,which alters a set of hypoxia-mediated miRNAs expression.These hypoxia-mediated miRNAs may exhibit either oncogenic activities or tumor-suppressive activities,mainly through the regulation of cellular pathways including hypoxia-inducible factors signaling.Acidic tumor microenvironment develops in hypoxic solid tumors due to a combination of predominant glycolytic metabolism(Warburg effect)and poor fluid clearance due to incomplete vascularization.In this review,we summarize our current understanding of the emerging roles of miRNAs in hypoxia and acidic tumor microenvironment.

Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

Background and Aims:Hepatitis B virus(HBV)infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics,by unknown mechanisms,in the generation of hepatocellular carcinoma.The pregnane X receptor(PXR)is a key regulator of the body’s defense against xenobiotics,including xenobiotic carcinogens and clinical drugs.In this study,we aimed to investigate the molecular mechanisms of HBV X protein(HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.Methods:The expression profile of PXR-cytochrome p4503A4(CYP3A4)signaling was determined by PCR,western blotting,and tissue microarray.Cell viability and aflatoxin B1(AFB1)cytotoxicity were measured using the cell counting kit-8 assay.Target gene expression was evaluated using transient transfection and real time-PCR.The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.Results:HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione Stransferase Mu 1(GSTM1)in cell lines.Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin(IL)-11:IL-11 receptor subunit alpha-1(IL11RA-1)-mediated inflammation in an HBx transgenic model.Conclusions:Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/GSTM1-KRASIL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.